compound of formula (I) ##STR1## in which: R1 and R2, which are identical or different, represent hydrogen or alkyl or alternatively R1 and R2 form, with the carbon atom which bears them, cycloalkyl,
R3 represents hydrogen or alkyl, phenyl or benzyl,
R4 represents:
optionally substituted amino, optionally substituted amindino, optionally substituted guanidino, optionally substituted isothioureido, optionally substituted iminomethylamino, mercapto substituted with heterocyclic, or heterocyclic,
R5 and R6 each represent hydrogen or alkyl, or ##STR2## forms a boronic ester of pinanediol, m represents an integer such that 0≦m≦6,
n represents an integer such that 1≦n≦6,
A represents any one of the following groups:
* optionally substituted bicycloalkyl (C5 -C10)phenyl,
* or a group of formula: ##STR3## A1 represents --CO--, --CS--, --SO2 --, the isomers thereof and the addition salts thereof with a pharmaceutically acceptable acid or base, and medicinal products containing the same are useful as trypsin-like serine proteases.
|
1. A compound selected from those of formula (I): ##STR24## in which: R1 and R2, which are identical or different, represent hydrogen or linear or branched (C1 -C6) alkyl or alternatively R1 and R2 form, with the carbon atom which bears them, a (C3 -C8) cycloalkyl,
R3 represents hydrogen or linear or branched (C1 -C6) alkyl, an optionally substituted phenyl or optionally substituted benzyl, R4 represents: amino optionally substituted with one or more identical or different linear or branched (C1 -C6) alkyl or optionally substituted benzyl, aryl, or heterocyclic groups, amidino optionally substituted with one or more identical or different linear or branched (C1 -C6) alkyl or optionally substituted benzyl, aryl, or heterocyclic groups, guanidino optionally substituted with a linear or branched (C1 -C6) alkyl or optionally substituted benzyl, aryl, or heterocyclic group, isothioureido optionally substituted with linear or branched (C1 -C6) alkyl or optionally substituted benzyl, aryl, or heterocyclic group, iminomethylamino optionally substituted with linear or branched (C1 -C6) alkyl, mercapto substituted with a heterocyclic group, or a heterocyclic group, R5 and R6 each represent hydrogen or linear or branched (C1 -C6) alkyl,
or ##STR25## forms a boronic ester of pinanediol, m represents zero to 6 inclusive, n represents one to 6 inclusive, A represents any one of the following groups: bicycloalkyl (C5 -C10) phenyl optionally substituted with one or more identical or different halogen atoms, linear or branched (C1 -C6) alkyl, linear or branched (C1 -C6) alkoxy, hydroxyl, or amino groups optionally substituted with one or two groups, which are identical or different, selected from linear or branched (C1 -C6) alkyl, and linear or branched (C1 -C6) alkylsulfonyl or arylsulfonyl, or a group of formula: ##STR26## on condition that, in this case, m is other than zero, in which: R7 and R8, which are identical or different, represent hydrogen, linear or branched (C1 -C6) alkyl optionally substituted with one or more aryl, heterocyclic, arylsulfonylamino, or (C5 -C10) bicycloalkyl phenyl which is optionally substituted with one or more groups as defined above under A or indanyl, linear or branched (C1 -C6) alkylsulfonyl, arylsulfonyl, aryl, heterocyclic, or bicycloalkyl (C5 -C10) phenyl which is optionally substituted with one or more groups as defined above under A, indanyl, or either of the groups: ##STR27## in which: Ra represent linear or branched (C1 -C6) alkyl or optionally substituted phenyl, Rb and Rc, which are identical or different, represent hydrogen or halogen or linear or branched (C1 -C6) alkyl, linear or branched (C1 -C6) alkoxy, hydroxyl, substituted or unsubstituted amino, or trihalomethyl, A2 represents --CO-- or --CS--, A1 represents --CO--, --CS--, or --SO2 --, the stereo and geometric isomers thereof, and the addition salts thereof with a pharmaceutically-acceptable acid or base.
4. A compound of
6. A compound of
7. A compound of
10. A compound of
12. A compound of
13. A compound of
15. A compound of
16. A compound of
17. A compound of
18. A compound of
19. A compound of
20. A compound of
21. A compound of
22. A compound of
23. A compound of
24. A method for treating a living body afflicted with a condition requiring an inhibitor of trypsin-like serine proteases comprising the step of administering to the living body an amount of a compound of
25. A method according to
26. A pharmaceutical composition useful as a protease inhibitor comprising as active principle an effective amount of a compound as claimed in
27. A compound of
|
The present invention relates to a new compounds derived from boronic acid and to their use as inhibitors of trypsin-like serine proteases.
1. Field of the Invention
One of these serine proteases, thrombin, is the key enzyme of coagulation and plays a central role in the pathology of venous and arterial thromboses, as shown by F. Toti et al., (Sang, Thrombose, Vaisseaux, 4, 483-494, 1992) and T. M. Reilly et al. (Blood Coagulation and Fibrinolysis, 3, 513-517, 1992).
Anti-thrombotic approaches are more effective and are without risk when compared with the current treatments. Direct inhibitors of thrombin, currently in clinical development, all have a series of advantages over heparin. However, these substances, hirudin and hirulog-1 have the disadvantage of not being active via the oral route.
Moreover, it is known that peptides containing the sequence (D)Phe-Pro-Arg are inhibitors of the catalytic site of thrombin (C. Kettner et al., J. Biol. Chem., 265(30), 18289-18297, 1990).
2. Prior Art Description
Peptide derivatives of boronic acid, having anti-thrombotic activity, have already been described in the literature. This is the case more particularly of the compounds described in patents EP 293,881 and EP 471,651. M. A. Hussain et al. have moreover demonstrated that Ac-(D)Phe-Pro-Arg boronic acid (DUP 714) is a thrombin inhibitor (Peptides, 12, 1153-1154, 1991).
3. Detailed Description of the Invention
It was thus particularly advantageous to synthesize novel inhibitors of serine proteases in order to increase the power and selectivity of the compounds already described in the literature. Furthermore, these compounds, which are no longer peptide derivatives, have different, increased coagulation times and activity via the oral route.
More specifically, the present invention relates to the compounds of formula (I): ##STR4## in which: R1 and R2, which are identical or different, represent a hydrogen atom or a linear or branched (C1 -C6) alkyl group or alternatively R1 and R2 form, with the carbon atom which bears them, a (C3 -C8)cycloalkyl group,
R3 represents a hydrogen atom or a linear or branched (C1 -C6) alkyl group, an optionally substituted phenyl group or an optionally substituted benzyl group,
R4 represents:
an amino group optionally substituted with one or more, identical or different, linear or branched (C1 -C6) alkyl groups, optionally substituted benzyl groups or aryl or heterocyclic groups,
an amidino group optionally substituted with one or more, identical or different, linear or branched (C1 -C6) alkyl groups, optionally substituted benzyl groups or aryl or heterocyclic groups,
a guanidino group optionally substituted with a linear or branched (C1 -C6) alkyl group, an optionally substituted benzyl group or an aryl or heterocyclic group,
isothioureido optionally substituted with a linear or branched (C1 -C6) alkyl group, an optionally substituted benzyl group or an aryl or heterocyclic group,
iminomethylamino optionally substituted with a linear or branched (C1 -C6) alkyl group,
mercapto substituted with a heterocyclic group,
or a heterocyclic group,
R5 and R6 each represent a hydrogen atom or a linear or branched (C1 -C6) alkyl group, or ##STR5## forms a boronic ester of pinanediol, m represents an integer such that 0≦m≦6,
n represents an integer such that 1≦n≦6,
A represents any one of the following groups:
* a bicycloalkyl (C5 -C10)phenyl group optionally substituted with one or more, identical or different, halogen atoms or linear or branched (C1 -C6) alkyl groups, linear or branched (C1 -C6) alkoxy groups, hydroxyl groups or amino groups (optionally substituted with one or two groups, which are identical or different, linear or branched (C1 -C6) alkyl, linear or branched (C1 -C6) alkylsulfonyl or arylsulfonyl),
* or a group of formula: ##STR6## on condition that, in this case, m is other than zero, in which:
R7 and R8, which are identical or different, represent a hydrogen atom, a linear or branched (C1 -C6) alkyl group (optionally substituted with one or more aryl, heterocyclic, arylsulfonylamino or (C5 -C10) bicycloalkyl phenyl groups optionally substituted with one or more groups as defined above or indanyl), a linear or branched (C1 -C6) alkylsulfonyl group, an arylsulfonyl group, an aryl group, a heterocyclic group or a bicycloalkyl (C5 -C10) phenyl group (optionally substituted with one or more groups as defined above), an indanyl group or either of the groups: ##STR7## in which: Ra represents a linear or branched (C1 -C6) alkyl group or an optionally substituted phenyl group,
Rb and Rc, which are identical or different, represent a hydrogen or halogen atom or a linear or branched (C1 -C6) alkyl group, a linear or branched (C1 -C6) alkoxy group, a hydroxyl group, a substituted or unsubstituted amino group or a trihalomethyl group,
A2 represents --CO-- or --CS--,
A represents --CO-- or --CS--,
A1 represents --CO--, --CS-- or --SO2 --,
the isomers thereof and the addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids which may be mentioned without any limitation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases which may be mentioned without any limitation are sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The term aryl group is understood to refer to phenyl, naphthyl or tetrahydronaphthyl, each of these groups optionally being substituted with one or more halogen atoms or linear or branched (C1 -C6) alkyl groups, (C3 -C7) cycloalkyl groups, (C5 -C10) bicycloalkyl groups, linear or branched (C1 -C6) alkoxy groups, hydroxyl or trihalomethyl groups or amino groups (optionally substituted with one or more linear or branched (C1 -C6) alkyl groups).
The term heterocyclic group is understood to refer to a saturated or unsaturated 5- to 12-membered mono- or bicyclic group containing one, two or three hetero atoms chosen from oxygen, nitrogen and sulfur, it being understood that the heterocycle may optionally be substituted with one or more halogen atoms or linear or branched (C1 -C6) alkyl groups, linear or branched (C1 -C6) alkoxy groups, hydroxyl or trihalomethyl groups, amino groups (optionally substituted with one or more linear or branched (C1 -C6) alkyl groups), imino or arylsulfonyl groups.
The term optionally substituted phenyl or benzyl group is understood to mean optionally substituted with one or more, identical or different, halogen atoms or linear or branched (C1 -C6) alkyl groups, linear or branched (C1 -C6) alkoxy groups, hydroxyl groups, substituted or unsubstituted amino groups or linear or branched (C1 -C6) trihaloalkyl groups.
The invention preferably relates to the compounds of formula (I) in which A1 represents --CO--, R3 represents a hydrogen atom and R4 represents an optionally substituted guanidino group.
In the definition of A, an optionally substituted bicycloalkyl (C5 -C10) phenyl group is preferably the optionally substituted (bicyclo[2.2.2]oct-1-yl)phenyl group. When A represents an optionally substituted bicycloalkyl (C5 -C10) phenyl group, m is preferably equal to 0.
When A represents the group ##STR8## A2 is preferably --CO--, R7 is preferably hydrogen and R8 is preferably a linear or branched (C1 -C6) alkyl group, preferably substituted with one or more aryl groups.
When A represents a group ##STR9## m is preferably equal to 1 and R1 and R2 form, with the carbon atom which bears them, a (C3 -C7) cycloalkyl group. A preferred cycoalkyl group for the definition of ##STR10## is the cyclopenyl group. The invention also covers the process for the preparation of the compounds of formula (I), characterized in that a compound of formula (II): ##STR11## in which R3 and n have the same meaning as in formula (I), R'5 and R'6 each represent a linear or branched (C1 -C6) alkyl group or ##STR12## forms a boronic ester of pinanediol, is reacted with a compound of formula (III): ##STR13## in which A, A1, R1, R2 and m have the same meaning as in formula (I),
X represents a chlorine atom or a hydroxyl group, to give the compound of formula (IV): ##STR14## in which A, A1, R1, R2, R3, R'5, R'6, m and n have the same meaning as above, which compound of formula (IV) may be converted, depending on the nature of the group R4 which it is desired to obtain:
either, into a corresponding cyano derivative by the action of copper cyanide and then reaction in alcoholic medium in the presence of acid, followed by the action of aqueous ammonia, into the corresponding amidino derivative of formula (I/a), a specific case of the compounds of formula (I): ##STR15## in which A, A1, R1, R2, R3, R'5, R'6, m and n have the same meaning as above, the amidino function of which compound is substituted, if so desired,
or, into the corresponding azido derivative by the action of sodium azide, and then catalytic hydrogenation into the corresponding amino derivative of formula (I/b), a specific case of the compounds of formula (I): ##STR16## in which A, A1, R1, R2, R3, R'5, R'6, m and n have the same meaning as above, the amine function of which compound of formula (I/b) is substituted, if so desired, and the amino group of which compound is converted, if so desired:
into a guanidino group by reaction with cyanamide, to give the compound of formula (I/c), a specific case of the compounds of formula (I); ##STR17## in which A, A1, R1, R2, R3, R'5, R'6, m and n have the same meaning as above and Rb represents a guanidino group, the guanidino function of which compound is substituted, if so desired,
or, into an iminomethylamino group by reaction with ethyl formimidate to give the compound of formula (I/d): ##STR18## in which A, A1, R1, R2, R3, R'5, R'6, m and n have the same meaning as above, the aminido function of which compound is substituted, if so desired,
either, by reaction with an optionally substituted thiourea, to give the compound of formula (I/e), a specific case of the compounds of formula (I): ##STR19## in which A, A1, R1, R2, R3, R'5, R'6, m and n have the same meaning as above and Rc represents an optionally substituted isothioureido group,
or, by reaction with a suitably protected heterocycle, an amine substituted with a suitably protected heterocycle or a thiol substituted with a suitably protected heterocycle, to give, after deprotection, the compound of formula (I/f), a specific case of the compounds of formula (I): ##STR20## in which A, A1, R1, R2, R3, R'5, R'6, m and n have the same meaning as above and Rd represents a heterocycle, an amino group substituted with a heterocycle or a mercapto group substituted with a heterocycle,
which compounds of formula (I/a), (I/b), (I/c), (I/d), (I/e) or (I/f) are converted, if so desired, using boron trichloride or phenylboronic acid, into the corresponding boronic acid of formula (I/g): ##STR21## in which A, A1, R1, R2, R3, R4, m and n have the same meaning as in formula (I),
which compounds of formula (I/a) to (I/g):
can, where appropriate, be purified according to a standard purification technique,
the isomers of which are, where appropriate, separated according to a standard separation technique,
are converted, if so desired, to its addition salts with a pharmaceutically acceptable base or acid.
The compounds of formula (II) are obtained:
either from the compound of formula (V) obtained according to the process described by M. W. Rathke et al. (J. Organomet. Chem. 122, 145-149, 1976): ##STR22## in which R3, R'5 and R'6 are as defined above, which compound is reacted with an organomagnesium reagent of formula (VI):
Br(CH2)n --MgCl (VI)
in which n, R3, R'5, and R'6, are as defined above, which reagent is reacted with 1,1,1,3,3,3-hexamethyldisilazane (HMDS) in the presence of n-butyllithium, to give, after treatment in acidic medium, the compound of formula (II),
or from an α-chloroboronic ester of formula (VII), prepared according to the process described by D. S. Matteson et al. (Organometallics, 3, 1284-1288, 1984) and W. Rathke et al. (J. Biol. Chem., 265(30), 18289-18297, 1990): ##STR23## in which R3, R'5, R'6, and n are as defined above, which compound is reacted with 1,1,1,3,3,3-hexamethyldisilazane (HMDS) in the presence of n-butyllithium to give, after treatment in acidic medium, the compound of formula (II).
The compound of formula (II) may also be obtained according to the process described by D. S. Matteson et al., (Organometallics, 3, 1284-1288, 1984) and W. Rathke et al. (J. Biol. Chem., 265(30), 18289-18297, 1990).
The compounds of formula (I/b), substituted or not on amino group, may also be obtained by reaction of a benzylamine eventually substituted with the compound of formula (IV).
Besides the fact that they are novel, the compounds of the present invention have particularly advantageous pharmacological properties.
They are powerful inhibitors of trypsin-like serine proteases which exhibit considerable selectivity towards thrombin when compared with other serine proteases of coagulation and of fibrinolysis. They moreover posses better activity via the oral route than the reference compound DUP 714.
These properties thus make them useful in the treatment of stable or unstable anginas, diseases of thrombotic origin and/or diseases which give rise to thrombotic complications, as well as in the treatment or prevention of myocardial infarction and venous or arterial thromboses and to prevent coagulation of blood in contact with e.g. containors and tubing.
They may also be used in therapeutic combinations with a thrombolytic agent.
The invention also covers pharmaceutical compositions containing, as active principal, at least one compound of formula (I) with one or more inert, non-toxic and suitable excipients. Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, simple or coated tablets, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions, etc.
The appropriate dosage can be adapted according to the nature and severity of the complaint, the route of administration and according to the age and weight of the patient. This dosage ranges from 1 to 500 mg per day in one or more dosage intakes.
The examples which follow illustrate the invention but do not limit it any way.
The starting materials used are known starting materials or are prepared according to known procedures.
Preparations A to Z and AA to AK lead to synthetic intermediates which are useful for the preparation of the compounds of the invention.
The structures of the compounds described in the examples were determined according to the usual spectrophotometric techniques (infrared, NMR, mass spectrometry, etc.).
Stage A: 4-(4-Methoxybicyclo[2.2.2]oct-1-yl)benzoic acid
The expected product is obtained according to the process described in patent EP 599,732.
Melting point: 239°C
Stage B: 4-(4-Methoxybicyclo[2.2.2]oct-1-yl)benzoyl chloride
10 mmol of phosphorus pentachloride are added to 10 mmol of the acid obtained in the above stage dissolved in carbon tetrachloride at 0° C. After warming to room temperature and stirring for 18 hours, the solution is evaporated. The residue is taken up in dichloromethane. The expected product is obtained after evaporation and drying.
Elemental microanalysis:
| ______________________________________ |
| C% H% N% |
| ______________________________________ |
| calculated |
| 68.94 6.87 12.72 |
| found 68.38 6.94 12.91 |
| ______________________________________ |
The expected product is obtained according to the process described in preparation A.
Stage A: 4-(4-Chlorobicyclo[2.2.2]oct-1yl)benzoic acid
Melting point: >260°C
Stage B: 4-(4-Chlorobicyclo[2.2.2]oct-1-yl)benzoyl chloride
Melting point: 128°C
Stage A: [4-(4-Methoxybicyclo[2.2.2]oct-1-yl]phenylacetic acid
The expected product is obtained according to the process described in patent EP 599,732.
Melting point: 220°C
Elemental microanalysis:
| ______________________________________ |
| C% H% |
| ______________________________________ |
| calculated |
| 74.42 8.08 |
| found 74.49 8.13 |
| ______________________________________ |
Stage B: [4-(4-Methoxybicyclo[2.2.2]oct-1-yl]phenylacetyl chloride
The corresponding acid chloride is obtained according to the process described in stage B of preparation A.
The expected product is obtained according to the process described in preparation A.
Stage A: 4-(4-Hydroxybicyclo[2.2.2]oct-1-yl)benzoic acid
Stage B: 4-(4-Hydroxybicyclo[2.2.2]oct-1-yl)benzoyl chloride
The expected product is obtained according to the process described in preparation A.
Stage A: 4-(2,4-Dimethoxybicyclo[2.2.2]oct-1-yl)benzoic acid
Stage B: 4-(2,4-Dimethoxybicyclo[2.2.2]oct-1-yl)benzoyl chloride
Elemental microanalysis:
| ______________________________________ |
| C% H% Cl% |
| ______________________________________ |
| calculated |
| 66.12 6.85 11.48 |
| found 65.58 6.75 12.23 |
| ______________________________________ |
Stage A: Monoethyl ester of cyclopentane-1,1-dicarboxylic acid
480 mmol of butyllithium are added to 480 mmol of diisopropylamine in 600 ml of anhydrous tetrahydrofuran (THF), under argon, at -70°C After stirring for 15 minutes at -70°C, 240 mmol of cyclopentanecarboxylic acid are added dropwise. After warming to room temperature, the mixture is heated for one hour at 50°C The reaction medium is then cooled to -70°C and 260 mmol of ethyl chloroformate are added. The solution is stirred for 20 minutes and then poured into ice-water. The medium is acidified with concentrated hydrochloric acid and then extracted with dichloromethane. The organic phase is then washed with water to neutral pH and then with saturated sodium chloride solution. After drying and evaporation, the expected product is obtained in the form of an oil.
Infrared (nujol): νCO =1702 cm-1
Stage B: Monoethyl ester of 1-benzylaminocarbonylcyclopentanecarboxylic acid
59 mmol of O-benzothiazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate are added to a solution containing 50 mmol of the compound obtained in the above stage, 59 mmol of benzylamine and 59 mmol of diisopropylethylamine in 100 ml of anhydrous dichloromethane. The medium is kept stirring overnight at room temperature. After evaporation of the solvent and uptake of the residue in ethyl acetate, the organic phase is washed, dried and evaporated to give the expected product in the form of an oil.
Stage C: 1-Benzylaminocarbonylcyclopentanecarboxylic acid
110 ml of 1N sodium hydroxide are added to a solution containing 55 mmol of the compound obtained in the above stage in 150 ml of THF. After 5 hours at room temperature, the THF is evaporated off. The aqueous phase is acidified and then extracted with ethyl acetate. The organic phase is then dried and evaporated. The expected product is then obtained by recrystallization of the residue from isopropyl ether.
Melting point: 92°-94°C
Preparations G to K were performed according to the process described in preparation F using the corresponding starting materials:
Melting point: 106°-108°C
Melting point: 126°-128°C
Infrared (nujol): νCO =1710 cm-1
Melting point: 112°-114°C
Melting point: 132°-134°C
PAC Preparation M: 4(4-Ethoxybicyclo[2.2.2]oct-1-yl)benzoyl chlorideThe expected product is obtained according to the process described in preparation A.
Stage A: 4-(4-Ethoxybicyclo[2.2.2]oct-1-yl)benzoic acid
Stage B: 4-(4-Ethoxybicyclo[2.2.2]oct-1-yl)benzoyl chloride
The expected product is obtained according to the process described in preparation A.
Stage A: 4-(4-Hydroxybicyclo[2.2.2]oct-1-yl)benzoic acid
Stage B: 4-(4-Hydroxybicyclo[2.2.2]oct-1-yl)benzoyl chloride
The expected product is obtained according to the process described in preparation A.
Stage A: 4-(4-Isopropylbicyclo[2.2.2]oct-1-yl)benzoic acid
Stage B: 4-(4-Isopropylbicyclo[2.2.2]oct-1-yl)benzoyl chloride
The expected product is obtained according to the process described in preparation A.
Preparations Q to Z and AA and AK were performed according to the process described in preparation F using the corresponding starting materials.
PAC Preparation R: 1-(N-Methylphenethylaminocarbonyl)cyclopentanecarboxylic acid PAC Preparation T: 1-(3-Methylphenethylaminocarbonyl)cyclopentanecarboxylic acid PAC Preparation V: 1-(3,4-Dimethoxybenzylaminocarbonyl)cyclopentanecarboxylic acid PAC Preparation X: 1-[2-(Pyrid-3yl)ethylaminocarbonyl]cyclopentanecarboxylic acid PAC Preparation Z: 1-(2,2-Diphenylethylaminocarbonyl)cyclopentanecarboxylic acid PAC Preparation AB: 1-[2-(Naphthalen-2-yl)ethylaminocarbonyl]cyclopentanecarboxylic acid PAC Preparation AD: 1-(3-Phenylpropylaminocarbonyl)cyclopentanecarboxylic acid PAC Preparation AF: 1-[4-(4-Methoxybicyclo[2.2.2]oct-1-yl)benzylaminocarbonyl]cyclopentanecarb oxylic acid PAC Preparation AH: 1-(Indan-2-ylmethylaminocarbonyl)cyclopentanecarboxylic acidThe expected product is obtained according to the process described in preparation A.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoyl amino]-4-aminobutylboronate hydrochlorideStage A: (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-bromobutylborona te
20 mmol of (+)-α-pinanediol 1-(R)-amino-4-bromobutylboronate, described in patent EP 615,978, are added to 20 mmol of the acid chloride described in preparation A in 130 ml of anhydrous dichloromethane. The reaction medium is cooled to -20°C and 44 mmol of triethylamine are added dropwise. After warming to room temperature and stirring for 18 hours, the mixture is evaporated. The residue is taken up in a water/ethyl acetate mixture. The organic phase is recovered and then washed with saturated aqueous sodium hydrogen carbonate solution, water, 10% citric acid and then saturated sodium chloride solution. After drying and evaporation, the expected product is obtained.
Stage B: (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-azidobutylborona te
15 mmol of the product obtained in the above stage in 30 ml of anhydrous dimethylformamide are placed at 100°C in the presence of 30 mmol of sodium azide for 4 hours. After 12 hours at room temperature, the mixture is taken up in an ethyl acetate/water mixture and the organic phase is washed several times with water, dried and evaporated to give the expected product.
Stage C: (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-aminobutylborona te hydrochloride
14 mmol of the compound obtained in the above stage in 250 ml of anhydrous methanol are hydrogenated in the presence of 2 mmol of chloroform using 50 mg of 10% palladium/C as catalyst, for 2 hours. After filtration of the catalyst, rinsing and evaporation, the expected product is obtained.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoyl amino]-4-guanidinobutylboronate hydrochloride10 mmol of the compound obtained in Example 1 and 100 mmol of cyanamide are refluxed in 80 ml of anhydrous ethanol for 2 days. After evaporation of the ethanol and passage through sephadex resin, taking up the residue in methanol, the expected product is obtained.
PAC 1-(R)-[4-(4-Methoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-guanidinobutylbor onic acid hydrochloride48 mmol of phenylboronic acid and 150 ml of 1N hydrochloric acid are added to 10 mmol of the compound obtained in Example 2 suspended in 150 ml of ethyl ether. The medium is stirred vigorously at room temperature and the aqueous phase is then separated out after settling has taken place, washed with ether and then brought to dryness. The expected product is obtained after purification of the residue by passage through Bio-gel P2 resin, using a 0.001N hydrochloric acid/acetonitrile mixture (1/1) as eluent.
Mass spectrum: FAB+ : [M+H]+ : m/z=417
PAC (+)-α-Pinanediol 1-(R)-[4-(4-chlorobicyclo[2.2.2]oct-1-yl)benzoylamino]-4-aminobutylboronat e hydrochlorideThe expected product is obtained according to the process described in Example 1, using the compound described in preparation B as starting material.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-chlorobicyclo[2.2.2]oct-1-yl)benzoylamino]-4-guanidinobutylbor onate hydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 4.
PAC 1-(R)-[4-(4-Chlorobicyclo[2.2.2]oct-1-yl)benzoylamino]-4-guanidinobutylboro nic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 5.
Mass spectrum: FAB+ : [M+H]+ : m/z=421
PAC (+)-α-Pinanediol 1-(R)-{[4-(4-methoxybicyclo[2.2.2]oct-1-yl)phenyl]acetylamino}-4-aminobuty lboronate hydrochlorideThe expected product is obtained according to the process described in Example 1, using the compound described in preparation C as starting material.
PAC (+)-α-Pinanediol 1-(R)-{[4-(4-methoxybicyclo[2.2.2]oct-1-yl)phenyl]acetylamino}-4-guanidino butylboronate hydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 7.
PAC 1-(R)-{[4-(4-Methoxybicyclo[2.2.2]oct-1-yl)phenyl]acetylamino}-4-guanidinob utylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 8.
Mass spectrum: FAB+ : [M+H]+ : m/z=431
PAC (+)-α-Pinanediol 1-(R)-[4-(4-hydroxybicyclo[2.2.2]oct-1-yl)benzoyl amino]-4-aminobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 1, using the compound described in preparation D as starting material.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-hydroxybicyclo[2.2.2]oct-1-yl)benzoyl amino]-4-guanidinobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 10.
PAC 1-(R)-[4-(4-Hydroxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-guanidinobutylbor onic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 11.
Mass spectrum: FAB+ : [M+H]+ : m/z=403
PAC (+)-α-Pinanediol 1-(R)-[2,4-dimethoxybicyclo[2.2.2]oct-1-yl)benzoyl amino]-4-aminobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 1, using the compound described in preparation E as starting material.
EXAMPLE 14
The expected product is obtained according to the process described in Example 2, using the compound described in Example 13 as starting material.
PAC 1-(R)-[4-(2,4-Dimethoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-guanidinobuty lboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, using the compound described in Example 14 as starting material.
Mass spectrum: FAB+ : [M+H]+ : m/z=447
PAC (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoyl amino]-4-(N-methylamino)butylboronate benzenesulfonate5.7 g of 3 Å molecular sieves and 3.75 ml of aqueous 40% formaldehyde solution are added to 1 mmol of the compound described in Example 1 in 20 ml of anhydrous ethanol. The mixture is stirred overnight at room temperature. After filtration, 1 mmol of benzenesulfonic acid is added to the ethanolic phases and the mixture is hydrogenated in the presence of 100 mg of 10% Pd/C as catalyst overnight at room temperature and at atmospheric pressure. The expected product is obtained after filtration of the catalyst and purification through Sephadex® resin.
PAC 1-(R)-[4-(4-Methoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-(N-methylamino)bu tylboronic acidThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 16.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-chlorobicyclo[2.2.2]oct-1-yl)benzoylamino]-4-(2-isothioureido) butylboronateStage A: (+)-α-Pinanediol 1-(R)-[4-(4-chlorobicyclo[2.2.2]oct-1-yl)benzoylamino]-4-bromobutylboronat
The expected product is obtained according to the process described in stage A of Example 1, using the compound described in preparation B as starting material.
Stage B: (+)-α-Pinanediol 1-(R)-[4-(4-chlorobicyclo[2.2.2]oct-1-yl)benzoylamino]-4-(2-isothioureido) butylboronate 2.4 mmol of the compound obtained in the above stage and 7.3 mmol of thiourea in 6 ml of ethanol are stirred for 60 hours at room temperature. After evaporation of the solvent, the expected product is obtained after purification by passage through "Sephadex®" resin, using methanol as eluent.
PAC 1-(R)-[4-(4-Chlorobicyclo[2.2.2]oct-1-yl)benzoylamino-4-(2-isothioureido)bu tylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 18.
Mass spectrum: FAB+ : [M+H]+ : m/z=438
PAC (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonylcyclopentanecarbox amido)-4-aminobutylboronate benzenesulfonateStage A: (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonylcyclopentanecarboxamido)-4-bromobutylboronate
10 mmol of N-methylmorpholine are added to 10 mmol of the compound described in preparation F in 50 ml of anhydrous THF. The mixture is placed under argon at -20°C, 10 mmol of isobutyl chloroformate are then added and the mixture is stirred for 20 minutes. 10 mmol of (+)-α-pinanediol 1-(R)-amino-4-bromobutylboronate (described in patent EP 615,978) in 50 ml of anhydrous THF are then added at -20° C., followed by dropwise addition of 20 mmol of anhydrous THF are then added at -20°C and then 12 hours at room temperature, the THF is evaporated off. The residue is taken up in ethyl acetate. The organic phase is washed, dried and evaporated. The expected product is obtained in the form of an oil after purification through a column of silica, using a dichloromethane/ethyl acetate mixture (8/2) as eluent.
Stage B: (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonylcyclopentanecarboxamido)-4-azidobutylboronate
The expected product is obtained according to the process described in stage B of Example 1, starting with the compound described in the above stage.
Stage C: (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonylcyclopentanecarboxamido)-4-aminobutylboronate benzenesulfonate
The expected product is obtained according to the process described in stage C of Example 1, starting with the compound described in the above stage and using benzenesulfonic acid in place of the chloroform.
PAC (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonylcyclopentanecarbox amido)-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 20.
PAC 1-(R)-(1-Benzylaminocarbonylcyclopentanecarboxamido)-4-guanidinobutylboroni c acid benzenesulfonate7 mmol of the compound obtained in Example 21 in a water/ether mixture (1/1) in the presence of 7 mmol of benzenesulfonic acid and 30 mmol of phenylboronic acid are stirred overnight. The aqueous phase is separated out after settling has taken place, it is concentrated and the expected product is obtained after purification through Biogel resin, using an acetonitrile/water mixture (1/1) as eluent.
Mass spectrum: FAB+ : [M+H]+ : m/z=404
PAC (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonylcyclobutanecarbox amido)-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation G as starting material.
PAC (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonylcyclobutanecarbox amido)-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 23.
PAC 1-(R)-(1-Benzylaminocarbonylcyclobutanecarboxamido)-4-guanidinobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 24.
Mass spectrum: FAB+ : [M+H]+ : m/z=390
PAC (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonylcyclohexanecarbox amido)-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation H as starting material.
PAC (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonylcyclohexanecarbox amido)-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 26.
PAC 1-(R)-(1-Benzylaminocarbonylcyclohexanecarboxamido)-4-guanidinobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 27.
Mass spectrum: FAB+ : [M+H]+ : m/z=418
PAC (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonylcyclopropanecarbox amido)-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation I as starting material.
PAC (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonylcyclopropanecarbox amido)-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 29.
PAC 1-(R)-(1-Benzylaminocarbonylcyclopropanecarboxamido)-4-guanidinobutylboroni c acid benzenesulfonateThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 30.
Mass spectrum: FAB+ : [M+H]+ : m/z=376
PAC (+)-α-Pinanediol 1-(R)-(2-benzylaminocarbonyl-2-methylpropion amido)-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation J as starting material.
PAC (+)-α-Pinanediol 1-(R)-(1-benzylaminocarbonyl-2-methylpropion amido)-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 32.
PAC 1-(R)-(2-Benzylaminocarbonyl-2-methylpropionamido)-4-guanidinobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 33.
Mass spectrum: FAB+ : [M+glycerol-2H2 O+H+ ]:m/z=434
PAC (+)-α-Pinanediol 1-(R)-(2-benzylaminocarbonyl-2-ethylbutylamido)-4-amidobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation K as starting material.
PAC (+)-α-Pinanediol 1-(R)-(2-benzylaminocarbonyl-2-ethylbutylamido)-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 35.
PAC 1-(R)-(2-Benzylaminocarbonyl-2-ethylbutylamido)-4guanidinobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 36.
Mass spectrum: FAB+ : [M+H]+ : m/z=406
PAC 1-(R)-[4-(4-Methoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-aminobutylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 1.
PAC 1-(R)-[4-(4-Chlorobicyclo[2.2.2]oct-1-yl)benzoylamino]-4-aminobutylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 4.
PAC 1-(R)-{[4-(4-Methoxybicyclo[2.2.2]oct-1-yl)phenyl]-acetylamino}-4-aminobuty lboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 7.
PAC 1-(R)-[4-(4-Hydroxybicyclo[2.2.2]oct-1yl)benzoylamino]-4-aminobutylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 10.
PAC 1-(R)-[4-(2,4-Dimethoxybicyclo[2.2.2]oct-1-yl)benzylamino]-4-aminobutylboro nic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 13.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1yl)benzoyl amino]-4-(2-isothioureido)butylboronateThe expected product is obtained according to the process described in Example 18, starting with the compound described in preparation A.
PAC 1-(R)-[4-(4-Methoxybicyclo[2.2.2]oct-1-yl)benzylamino]-4-(2-isothioureido)b utylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 43.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-5-aminopentylboron ate hydrochlorideThe expected product is obtained according to the process described in Example 1, using the compound described in preparation A and (+)-α-pinanediol 1-(R)-amino-5-bromopentylboronate, described in patent EP 615,978, as starting materials.
PAC 1-(R)-[4-(4-Methoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-5aminopentylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 45.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoyl amino]-5-guanidinobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 45.
PAC 1-(R)-[4-(4-Methoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-5-guanidinopentylbo ronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 47.
PAC (+)-α-Pinanediol 1-(R)-[3-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoyl amino]-4-aminobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 1, using the compound described in preparation L as starting material.
PAC (+)-α-Pinanediol 1-(R)-[3-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoyl amino]-4-guanidinobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 49.
PAC 1-(R)-[3-(4-Methoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-guanidinobutylbor onic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 50.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-ethoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-aminobutylboronat e hydrochlorideThe expected product is obtained according to the process described in Example 1, using the compound described in preparation M as starting material.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-ethoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-guanidinobutylbor onate hydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 52.
PAC 1-(R)-[4-(4-Ethoxybicyclo[2.2.2]oct-1-yl)benzoylamino]-4-guanidinobutylboro nic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 53.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoyl amino]-4-(N-methylguanidino)butylboronate hydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 16.
PAC 1-(R)-[4-(4-Methoxybicyclo[2.2.2]oct-1yl)benzoylamino]-4-(N-methylguanidino )butylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 55.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo2.2.2]oct-1-yl)benzoylamino]-4-(iminomethylamino )butylboronate hydrochlorideThe expected product is obtained by reacting ethyl formimidate, with the compound described in Example 1, according to the process described in U.S. Pat. No. PCT 94/04058.
PAC 1-(R)-[4-(4-Methoxybicyclo[2.2.2]oct-1yl)benzoylamino]-4-(iminomethylamino) butylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 57.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1-yl)benzoyl amino]-4-[iminomethyl(N-methyl)amino]butylboronate hydrochlorideThe expected product is obtained according to the process described in Example 57, starting with the compound described in Example 16.
PAC 1-(R)-[4-(4-Methoxybicyclo[2.2.2]oct-1yl)benzoylamino]-4-[iminomethyl-(N-me thyl)amino]butylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 59.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1yl)benzoyl amino]-4-(2-isothioureido)butylboronateThe expected product is obtained according to the process described in Example 18, stage B, starting with the compound described in Example 1, stage A.
PAC 1-(R)-[4-(4-Methoxybicyclo[2.2.2]oct-1yl)benzoylamino]-4-(2-isothioureido)b utylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 61.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-chlorobicyclo[2.2.2]oct-1yl)benzoylamino]-5-aminopentylboronat e hydrochlorideThe expected product is obtained according to the process described in Example 45, using the compound described in preparation B as starting material.
PAC 1-(R)-[4-(4-Chlorobicyclo[2.2.2]oct-1-yl)benzoylamino]-5-aminopentylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 63.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-chlorobicyclo[2.2.2]oct-1yl)benzoylamino]-5-guanidinopentylbor onate hydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 63.
PAC 1-(R)-[4-(4-Chlorobicyclo[2.2.2]oct-1-yl)benzoylamino]-5-guanidinopentylbor onic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 65.
PAC (+)-α-Pinanediol 1-(R)-[3-(4-hydroxybicyclo[2.2.2]oct-1yl)benzoyl amino]-4-aminobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 1, using the compound described in preparation N as starting material.
PAC (+)-α-Pinanediol 1-(R)-[3-(4-hydroxybicyclo[2.2.2]oct-1yl)benzoyl amino]-4-guanidinobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 67.
PAC 1-(R)-[3-(4-Hydroxybicyclo[2.2.2]oct-1yl)benzoylamino]-4-guanidinobutylboro nic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, using the compound described in example 68.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-isopropylbicyclo[2.2.2]oct-1yl)benzoyl amino]-4-aminobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 1, using the compound described in preparation O as starting material.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-isopropylbicyclo[2.2.2]oct-1yl)benzoyl amino]-4-guanidinobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 70.
PAC 1-(R)-[4-(4-Isopropylbicyclo[2.2.2]oct-1yl)benzoylamino]-4-guanidinobutylbo ronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 71.
PAC (+)-α-Pinanediol 1-(R)-[4-(bicyclo[2.2.2]oct-1yl)benzoylamino]-4-aminobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 1, using the compound described in preparation P as starting material.
PAC (+)-α-Pinanediol 1-(R)-[4-(bicyclo[2.2.2]oct-1yl)benzoylamino]-4-guanidinobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 73.
PAC 1-(R)-[4-(Bicyclo[2.2.2]oct-1yl)benzoylamino]-4-guanidinobutylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 74.
PAC (+)-α-Pinanediol 1-(R)-[4-(4-methoxybicyclo[2.2.2]oct-1yl)benzoyl amino]-4-(1-methylimidazol-2-yl)thiobutylboronateThe expected product is obtained by reacting 1-methyl-2-mercaptoimidazole with the compound described in Example 1, stage A, according to the process described in patent EP 401,462.
PAC 1-(R)-[4-(4-Methoxybicyclo[2.2.2]oct-1yl)benzoylamino]-4-(1-methylimidazol- 2yl)thiobutylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 76.
PAC (+)-α-Pinanediol 1-(R)-(1-phenethylaminocarbonycyclopentanecarboxamido)-5-aminopentylborona te hydrochlorideThe expected product is obtained according to the process described in Example 20, using the compound described in preparation Q and (+)-α-pinanediol 1-(R)-amino-5-bromopentylboronate, described in patent EP 615,978, as starting materials and replacing the benzenesulfonic acid with chloroform.
PAC 1-(R)-(1-Phenethylaminocarbonylcyclopentanecarboxamido)-5-aminopentylboroni c acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 78.
PAC (+)-α-Pinanediol 1-(R)-(1-phenethylaminocarbonylcyclopentanecarboxamido)-4-aminobutylborona te hydrochlorideThe expected product is obtained according to the process described in Example 20, using the compound described in preparation Q as starting material and replacing at stage C benzenesulfonic acid with chloroform.
PAC 1-(R)-(1-Phenethylaminocarbonylcyclopentanecarboxamido)-4-aminobutylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 80.
PAC (+)-α-Pinanediol 1-(R)-(1-phenethylaminocarbonylcyclopentanecarboxamido)-4-guanidinobutylbo ronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 80 in the form of benzenesulfonate.
PAC 1-(R)-(1-Phenethylaminocarbonylcyclopentanecarboxamido)-4-guanidinobutylbor onic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 82.
PAC (+)-α-Pinanediol 1-(R)-(1-phenethylaminocarbonylcyclopentanecarboxamido)-4-(4-imino-4H-pyri d-1-yl)butylboronate hydrochlorideStage A: (+)-α-Pinanediol 1-(R)-(1-phenethylaminocarbonylcyclopentanecarboxamido)-4-bromobutylborona te
The expected product is obtained according to the process described in Example 20, stage A, using the compound described in preparation Q as starting material.
Stage B: (+)-α-Pinanediol 1-(R)-(1-phenethylaminocarbonylcyclopentanecarboxamido)-4-(4-imino-4H-pyri d-1-yl)butylboronate hydrochloride
The expected product is obtained according to the process described in stage B of Example 1, starting with the compound described in the above stage, using 4-aminopyridine in place of the sodium azide.
PAC 1-(R)-(1-Phenethylaminocarbonylcyclopentanecarboxamido)-4-(4-imino-4H-pyrid -1-yl)butylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 84.
PAC (+)-α-Pinanediol 1-(R)-[1-(N-methylphenethylaminocarbonyl)cyclo pentanecarboxamido]-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation R as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(N-methylphenethylaminocarbonyl)cyclo pentanecarboxamido]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 86.
PAC 1-(R)-[1-(N-Methylphenethylaminocarbonyl)cyclopentanecarboxamido]-4-guanidi nobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 87.
PAC (+)-α-Pinanediol 1-(R)-[1-(3,5-bistrifluoromethylbenzylaminocarbonyl) cyclopentanecarboxamido]-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation S as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(3,5-bistrifluoromethylbenzylaminocarbonyl)-cyclopentanecarboxami do]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 89.
PAC 1-(R)-[1-(3,5-bistrifluoromethylbenzylaminocarbonyl)cyclopentanecarboxamido ]-4-guanidinobutyl boronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 90.
PAC (+)-α-Pinanediol 1-(R)-[1-(3-methoxyphenethylaminocarbonyl)cyclopentanecarboxamido]-4-amino butylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation T as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(3-methoxyphenethylaminocarbonyl)cyclo pentanecarboxamido]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 92.
PAC 1-(R)-[1-(3-Methoxyphenethylaminocarbonyl)cyclopentanecarboxamido]-4-guanid inobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 93.
PAC (+)-α-Pinanediol 1-(R)-[1-(4-hydroxyphenethylaminocarbonyl)cyclo pentanecarboxamido]-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation U as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(4-hydroxyphenethylaminocarbonyl)cyclo pentanecarboxamido]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 95.
PAC 1-(R)-[1-(4-Hydroxyphenethylaminocarbonyl)cyclopentanecarboxamido]-4-guanid inobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 96.
PAC (+)-α-Pinanediol 1-(R)-[1-(3,4-dimethoxybenzylaminocarbonyl)cyclo pentanecarboxamido]-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation V as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(3,4-dimethoxybenzylaminocarbonyl)cyclo pentanecarboxamido]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 98.
PAC 1-(R)-[1-(3,4-Dimethoxybenzylaminocarbonylcyclopentanecarboxamido]-4-guanid inobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 99.
PAC (+)-α-Pinanediol 1-(R)-[1-(3,4-dimethoxyphenethylaminocarbonyl)cyclopentanecarboxamido]-4-a minobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation W as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(3,4-dimethoxyphenethylaminocarbonyl)cyclopentanecarboxamido]-4-g uanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 101.
PAC 1-(R)-[1-(3,4-Dimethoxyphenethylaminocarbonyl)cyclopentanecarboxamido]-4-gu anidinoboronic acid benzensulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 102.
PAC (+)-α-Pinanediol 1-(R)-{1-[2-(pyrid-3-yl)ethylaminocarbonyl]cyclo pentanecarboxamido}-4-aminobutylboronate dihydrochlorideThe expected product is obtained according to the process described in Example 20, using the compound described in preparation X as starting material and replacing the benzenesulfonic acid with chloroform.
PAC (+)-α-Pinanediol 1-(R)-{1-[2-(pyrid-3-yl)ethylaminocarbonyl]cyclo pentanecarboxamido}-4-guanidinobutylboronate dihydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 104.
PAC 1-(R)-{1-[2-(Pyrid-3-yl)ethylaminocarbonyl]cyclopentanecarboxamido}-4-guani dinobutylboronic acid dihydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 105.
PAC (+)-α-Pinanediol 1-(R)-1-(benzhydrylaminocarbonylcyclopentane carboxamido)-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation Y as starting material.
PAC (+)-α-Pinanediol 1-(R)-1-(benzhydrylaminocarbonylcyclopentane carboxamido)-4-guanidinoboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 107.
PAC 1-(R)-1-(Benzhydrylaminocarbonylcyclopentanecarboxamido)-4-guanidinoboronic acid benzensulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 108.
PAC (+)-α-Pinanediol 1-(R)-[1-(2,2-diphenylethylaminocarbonyl)cyclo pentanecarboxamido]-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation Z as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(2,2-diphenylethylaminocarbonyl)cyclo pentanecarboxamido]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 110.
PAC 1-(R)-[1-(2,2-Diphenylethylaminocarbonyl)cyclopentanecarboxamido]-4-guanidi nobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 111.
PAC (+)-α-Pinanediol 1-(R)-[1-(naphthalen-2-ylmethylaminocarbonyl)cyclopentanecarboxamido]-4-am inobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation AA as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-naphthalen-2-ylmethylaminocarbonyl)cyclopentanecarboxamido]-4-gua nidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 113.
PAC 1-(R)-[1-(Naphthalen-2-ylmethylaminocarbonyl)cyclopentanecarboxamido]-4-gua nidinobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 114.
PAC (+)-α-Pinanediol 1-(R)-{1-[2-(naphthalen-2-yl)ethylaminocarbonyl]cyclopentanecarboxamido}-4 -aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation AB as starting material.
PAC (+)-α-Pinanediol 1-(R)-{1-[2-naphthalen-2-yl)ethylaminocarbonyl]cyclopentanecarboxamido}-4- guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 116.
PAC 1-(R)-{1-[2-(Naphthalen-2-yl)ethylaminocarbonyl]cyclopentanecarboxamido}-4- guanidinobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 117.
PAC (+)-α-Pinanediol 1-(R)-[1-(1,1-dimethyl-2-phenylethylaminocarbonyl)-cyclopentanecarboxamido ]-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation AC as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(1,1-dimethyl-2-phenylethylaminocarbonyl)-cyclopentanecarboxamido ]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 119.
PAC 1-(R)-[1-(1,1-Dimethyl-2-phenylethylaminocarbonyl)cyclopentanecarboxamido]- 4-guanidinobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 120.
PAC (+)-α-Pinanediol 1-(R)-[1-(3-phenylpropylaminocarbonyl)cyclopentanecarboxamido]-4-aminobuty lboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation AD as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(3-phenylpropylaminocarbonyl)cyclopentanecarboxamido]-4-guanidino butylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 122.
PAC 1-(R)-[1-(3-Phenylpropylaminocarbonyl)cyclopentanecarboxamido]-4-guanidinob utylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 123.
PAC (+)-α-Pinanediol 1-(R)-[1-(2-benzensulfonylaminoethylaminocarbonyl)-cyclopentanecarboxamido ]-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation AE as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(2-benzenesulfonylaminoethylaminocarbonyl)-cyclopentanecarboxamid o]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 125.
PAC 1-(R)-[1-(2-Benzenesulfonylaminoethylaminocarbonyl)cyclopentanecarboxamido] -4-guanidinobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 126.
PAC (+)-α-Pinanediol 1-(R)-{1-[4-(4-methoxybicyclo[2,2,2]oct-1-yl)benzyl aminocarbonyl]cyclopentanecarboxamido}-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation AF as starting material.
PAC (+)-α-Pinanediol 1-(R)-{1-[4-(4-methoxybicyclo[2,2,2]oct-1-yl)benzyl aminocarbonyl]cyclopentanecarboxamido}-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 128.
PAC 1-(R)-{1-[4-(4-Methoxybicyclo[2,2,2]oct-1-yl)benzylaminocarbonyl]cyclopenta necarboxamido}-4-guanidinobutylboronic acid enzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 129.
PAC (+)-α-Pinanediol 1-(R)-[1-(indan-2-ylaminocarbonyl)cyclopentane carboxamido]-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation AG as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(indan-2-ylaminocarbonyl)cyclopentane carboxamido]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 131.
PAC 1-(R)-[1-(Indan-2-ylaminocarbonyl)cyclopentanecarboxamido]-4-guanidinobutyl boronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 132.
PAC (+)-α-Pinanediol 1-(R)-[1-(indan-2-ylmethylaminocarbonyl)cyclo pentanecarboxamido]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation AH as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(indan-2-ylmethylaminocarbonyl)cyclo pentanecarboxamido]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 134.
PAC 1-(R)-[1-(Indan-2-ylmethylaminocarbonyl)cyclopentanecarboxamido]-4-guanidin obutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 135.
PAC (+)-α-Pinanediol 1-(R)-[1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylaminocarbonyl)cyclo pentanecarboxamido]-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation AI as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylaminocarbonyl)cyclo pentanecarboxamido]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 137.
PAC 1-(R)-[1-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylaminocarbonyl)cyclop entanecarboxamido]-4-guanidinobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 138.
PAC (+)-α-Pinanediol 1-(R)-[1-(6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-ylaminocarbon yl)cyclopentanecarboxamido]-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation AJ as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1-(6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-ylaminocarbon yl)cyclopentanecarboxamido]-4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 140.
PAC 1-(R)-[1-(6,11-Dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-ylaminocarbony l)cyclopentanecarboxamido]-4-guanidinobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 141.
PAC (+)-α-Pinanediol 1-(R)-[1-(1-benzenesulfonylpiperid-4-ylaminocarbonyl)cyclopentanecarboxami do]-4-aminobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 20, using the compound described in preparation AK as starting material.
PAC (+)-α-Pinanediol 1-(R)-[1benzenesulfonylpiperid-4-ylaminocarbonyl)cyclopentanecarboxamido]- 4-guanidinobutylboronate benzenesulfonateThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 143.
PAC 1-(R)-[1-(1-Benzenesulfonylpiperid-4-ylaminocarbonyl)cyclopentanecarboxamid o]-4-guanidinobutylboronic acid benzenesulfonateThe expected product is obtained according to the process described in Example 22, starting with the compound described in Example 144.
PAC (+)-α-Pinanediol 1-(R)-{2-[1-(4-methoxybicyclo[2.2.2]oct-1-yl)-1-methyl]ethylcarbonylamino} -4-aminobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 1, using the product described in preparation AL as starting material.
PAC (+)-α-Pinanediol 1-(R)-{2-[1-(4-methoxybicyclo[2.2.2]oct-1-yl)-1-methyl]ethylcarbonylamino} -4-guanidinobutylboronate hydrochlorideThe expected product is obtained according to the process described in Example 2, starting with the compound described in Example 146.
PAC 1-(R)-{2-[1-(4-Methoxybicyclo[2.2.2]oct-1-yl)-1-methyl]ethylcarbonylamino}- 4-guanidinobutylboronic acid hydrochlorideThe expected product is obtained according to the process described in Example 3, starting with the compound described in Example 147.
PAC EXAMPLE 149Anticoagulant activity, measurement of the thrombin time and the activated cephalin time in man
In order to evaluate the anticoagulant activity of the compounds of the invention, the thrombin time (TT) and the activated cephalin time (ACT) were determined in samples of human plasma. An ST4 coagulometer (Diagnostica Stago, France) was used. In healthy volunteers, samples of venous blood were taken from the crook of the elbow, onto trisodium citrate solution (0.109M). A platelet-poor plasma is obtained by centrifugation of the blood samples (3000 g, 15 minutes). The TT is determined with the Thrombin Prest reagent and the ACT with the Automat Cephalin PTT reagent.
The inhibitor or the solvent (10 μl) is added to the plasma (90 μl), then the mixture is incubated for 2 minutes at 37°C 100 μl of Thrombin Prest (TT) or of Automat Cephalin PTT (ACT) are added while starting the chronometer.
Under these conditions, the TT is about 18 seconds and the ACT is about 12 seconds. The activity of an antagonist is evaluated by its capacity to prolong the TT and the ACT relative to the control. The effect of the inhibitors is expressed by the concentration in μM which multiplies the coagulation time by 2 (Ctt2).
The compounds of the invention produced very large prolongations of the coagulation times, and the Ctt2 values are shown by way of example of the table below:
| ______________________________________ |
| Products TT Ctt2 (μM) |
| ACT Ctt2 (μM) |
| ______________________________________ |
| Ex. 3 0.32 1.25 |
| Ex. 22 0.30 1.58 |
| Ex. 6 0.75 3.13 |
| Ex. 12 0.18 0.78 |
| Ex. 83 0.13 0.56 |
| Ex. 51 0.15 0.84 |
| Ex. 103 0.29 1.67 |
| Ex. 94 0.32 1.77 |
| Ex. 69 0.17 0.56 |
| ______________________________________ |
To evaluate in vitro the inhibitory activity of the products of the invention on human thrombin (Sigma, specific activity 3230 UNIH/mg), purified human fibrinogen (4 mM, Stago) (Fg) was added to a given amount of thrombin (0.7 nM) preincubated with or without the test inhibitor (20°C, 10 minutes).
To evaluate in vitro the selectivity of these products towards various serine proteases of fibrinolysis, the same procedure was applied to purified human plasmid (2 nM, Stage), to plasminogen tissue activator (t-PA) (2 nM, Calbiochem) and to purified human urokinase (u-PA) (2 nM, Sigma), using various para-nitroanilide peptides as substrates: <Glu-Phe-Lys-pNA (0.05 mM, S 2403, Kabi), H-D-Ile-Pro-Arg-pNA (0.48 mM, S 2288, Kabi), <Glu-Gly-Arg-pNA (0.56 mM, S 2444, Kabi).
Inhibitors, enzymes and substrates are diluted in the same buffer (0.01 mM phosphate buffer, pH 7.4, containing 0.12M sodium chloride and 0.05% bovine serum albumin) and then distributed in a polystyrene microplate under a volume of 50 μl.
The fibrin formed by the thrombin or by the para-nitroanilide released by the action of the serine protease is measured spectrophotometrically at 405 nm after reaction for 15 to 30 minutes at 20°C
The table below gives the concentration of the compounds in nM which inhibits the enzymatic activity by 50% (IC50) relative to the product-free control. The results obtained demonstrate that the compounds of the invention are powerful inhibitors of human thrombin with respect to human fibrinogen. The compounds posses a very considerable selectivity towards the serine proteases of fibrinolysis.
The table below shows, by way of example, the results obtained for the compounds of the invention:
| ______________________________________ |
| IC50 (nM) |
| Products Thrombin Plasmin t-PA u-PA |
| ______________________________________ |
| Ex. 3 9.3 1960 810 >33 000 |
| Ex. 22 4.9 8630 1350 780 |
| Ex. 6 9.7 2041 290 30 000 |
| Ex. 12 6.6 2104 93 15 400 |
| Ex. 83 2.4 6885 1558 1205 |
| Ex. 51 2.7 531 1537 5610 |
| Ex. 103 4.0 3282 1436 1022 |
| Ex. 94 3.9 4058 1406 1002 |
| Ex. 69 6.5 692 709 >33 000 |
| ______________________________________ |
Male or female dogs weighing 11-28 kg are treated orally with the products of the invention (5 mg/kg) or with the reference substance, DUP 714, at a concentration of 2.5 mg/kg. The coagulation times (TT, ACT) are determined in samples of plasma from the dogs 10 min before and 30 min, 1 hour, 2 hours, 4 hours and 6 hours after administration of the products. The coagulation times are measured as described in Example 148. The number of platelets is also determined in each sample using a T450 counter (Coultronics).
Under the conditions of our experiments, the number of platelets before the treatment is about 300,000 platelets/μl; the TT is about 19 seconds and the ACT is about 18 seconds.
The reference substance used at a dose of 2.5 mg/kg lowers the number of platelets appreciably and reversibly; at 1 hour after its administration, the number of platelets falls by 55±14% (see table below). Such thrombopenias are not observed with the substances of the invention used at higher doses than DUP 714, except in Example 12:
Thrombopenias observed 1 hour after oral administration to dogs
| ______________________________________ |
| Products % |
| ______________________________________ |
| DUP 714 (2.5 mg/kg) 55% |
| Ex. 3 0% |
| Ex. 22 0% |
| Ex. 6 0% |
| Ex. 12 40% |
| Ex. 83 0 |
| Ex. 51 0 |
| Ex. 103 0 |
| Ex. 94 0 |
| Ex. 69 0 |
| ______________________________________ |
DUP 714 and the substances of the invention appreciably increase the TT and the ACT in animals. Table B summarizes the results obtained. The results appear 1 hour and 4 hours after oral administration of 2.5 mg/kg of DUP 714 and 5 mg/kg of the substances of the invention. The values show the number of times that the initial time is increased.
Increases in TT and ACT in dogs after oral administration
| ______________________________________ |
| TT ACT |
| 1 hour 4 hours 1 hour 4 hours |
| ______________________________________ |
| Ex. 3 16 12 19 14 |
| Ex. 22 20 8 6 2 |
| Ex. 6 30 10 4 2 |
| Ex. 12 24 19 >30 >30 |
| Ex. 83 >30 18 7 4 |
| Ex. 51 22 19 3 2 |
| Ex. 103 >30 24 6 4 |
| Ex. 94 17 21 9 4 |
| Ex. 69 18 15 4 3 |
| ______________________________________ |
Preparation formulation for 1000 tables containing a 10 mg dose:
Compound of Example 1 . . . 10 g
Hydroxypropylcellulose . . . 2 g
Wheat starch . . . 10 g
Lactose . . . 100 g
Magnesium stearate . . . 3 g
Talc . . . 3 g
Verbeuren, Tony, De Nanteuil, Guillaume, Rupin, Alain, Portevin, Bernard, Simonet, Serge, Lila, Christine, Gloanec, Philippe
| Patent | Priority | Assignee | Title |
| 6586615, | Jan 10 2001 | BRISTOL-MYERS SQUIBB COMPANY FORMERLY D B A DUPONT PHARMACEUTICALS COMPANY | α-aminoboronic acids prepared by novel synthetic methods |
| 7112572, | Sep 09 2002 | Paion Deutschland GmbH | Multivalent metal salts of boronic acids |
| 7371729, | Sep 09 2002 | Paion Deutschland GmbH | Boronic acid salts useful in parenteral formulations |
| 7514579, | Jun 13 2002 | JOHNS HOPKINS UNIVERSITY, JOHNS HOPKINS TECHNOLOGY TRANSFER | Boronic chalcone derivatives and uses thereof |
| 7838673, | Oct 16 2007 | MILLENIUM PHARMACEUTICALS, INC | Proteasome inhibitors |
| 8445432, | Oct 30 2009 | NTF THERAPEUTICS, INC | Neurturin molecules |
| 9127083, | Oct 30 2009 | NTF THERAPEUTICS, INC | Neurturin molecules |
| 9469679, | Oct 30 2009 | NTF Therapeutics, Inc. | Neurturin molecules |
| 9481709, | Dec 03 2007 | OBE THERAPY BIOTECHNOLOGY | Boropeptide inhibitors of enteropeptidase and their uses in treatment of obesity, overweight and/or diseases associated with an abnormal fat metabolism |
| Patent | Priority | Assignee | Title |
| 5187157, | Jun 05 1987 | Bristol-Myers Squibb Pharma Company | Peptide boronic acid inhibitors of trypsin-like proteases |
| 5563127, | Mar 24 1993 | Bristol-Myers Squibb Pharma Company | Boronic acid and ester inhibitors of thrombin |
| 5574017, | Jul 05 1994 | Antibacterial agents | |
| EP471651, |
| Executed on | Assignor | Assignee | Conveyance | Frame | Reel | Doc |
| Feb 25 1997 | DE NANTEUIL, GUILLAUME | Adir et Compagnie | ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS | 008566 | /0268 | |
| Feb 25 1997 | GLOANEC, PHILIPPE | Adir et Compagnie | ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS | 008566 | /0268 | |
| Feb 25 1997 | LILA, CHRISTINE | Adir et Compagnie | ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS | 008566 | /0268 | |
| Feb 25 1997 | PORTEVIN, BERNARD | Adir et Compagnie | ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS | 008566 | /0268 | |
| Feb 25 1997 | VERBEUREN, TONY | Adir et Compagnie | ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS | 008566 | /0268 | |
| Feb 25 1997 | RUPIN, ALAIN | Adir et Compagnie | ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS | 008566 | /0268 | |
| Feb 25 1997 | SIMONET, SERGE | Adir et Compagnie | ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS | 008566 | /0268 | |
| Feb 27 1997 | Adir et Compagnie | (assignment on the face of the patent) | / | |||
| Jul 30 2001 | Adir et Compagnie | LES LABORATOIRES SERVIER | MERGER SEE DOCUMENT FOR DETAILS | 012475 | /0568 |
| Date | Maintenance Fee Events |
| Feb 18 2002 | M183: Payment of Maintenance Fee, 4th Year, Large Entity. |
| Apr 19 2006 | REM: Maintenance Fee Reminder Mailed. |
| Sep 29 2006 | EXP: Patent Expired for Failure to Pay Maintenance Fees. |
| Date | Maintenance Schedule |
| Sep 29 2001 | 4 years fee payment window open |
| Mar 29 2002 | 6 months grace period start (w surcharge) |
| Sep 29 2002 | patent expiry (for year 4) |
| Sep 29 2004 | 2 years to revive unintentionally abandoned end. (for year 4) |
| Sep 29 2005 | 8 years fee payment window open |
| Mar 29 2006 | 6 months grace period start (w surcharge) |
| Sep 29 2006 | patent expiry (for year 8) |
| Sep 29 2008 | 2 years to revive unintentionally abandoned end. (for year 8) |
| Sep 29 2009 | 12 years fee payment window open |
| Mar 29 2010 | 6 months grace period start (w surcharge) |
| Sep 29 2010 | patent expiry (for year 12) |
| Sep 29 2012 | 2 years to revive unintentionally abandoned end. (for year 12) |